This Mentored Patient-Oriented Career Development Award focuses on developing expertise in the interdisciplinary field of perimenopausal depression. Menopause is universal in women, and depressive disorders occur in 10% of perimenopausal women. This project will dissect the mechanisms by which estrogen replacement therapy (ERT) treats depression in menopausal women. We hypothesize that ERT improves mood by a direct CNS effect, rather than by simply treating hot flushes and sleep disruption. A physiologic intervention study will compare the mood effect of ERT with that of a hypnotic agent in depressed perimenopausal women. The direct neuromodulatory effect of ERT on mood will be unmasked by controlling for ERT's effect on sleep. Polysomnographic (PSG) studies will be used to explore changes in sleep architecture that occur with ERT and the hypnotic agent zolpidem. This study will: (1) identify the elements critical to estrogen's antidepressant benefit; (2) characterize subpopulations of perimenopausal women whose depression can be treated with non-hormonal therapies and those who require treatment with ERT; and (3) define optimal management of depression in perimenopausal women. Understanding the components of ERT's effect on mood will also advance the field of hot-flush research by examining the impact of hot flushes on sleep, mood, and quality-of-life. This is critical for the development of novel estrogen alternatives and putative hot-flush therapies increasingly used in women with breast cancer and others unable or unwilling to take ERT. ENVIRONMENT: The proposed study will be based at Massachusetts General Hospital (MGH), with outstanding interdisciplinary sponsorship and consultant input. PSG studies will be performed at McLean Hospital. I will receive mentorship from Lee Cohen, M.D., in the Department of Psychiatry, and Janet Hall, M.D., in the Reproductive Endocrinology Unit of the Department of Medicine at MGH. Both sponsors are internationally recognized in their respective fields and have exceptional track records as effective research mentors. Their combined expertise will shape my career development in this interdisciplinary field. CAREER DEVELOPMENT PLAN: Physiologic investigation of mood disturbance in menopausal women requires that I acquire knowledge of (1) sleep medicine; and (2) research methods for healthoutcomes assessment and clinical intervention studies using physiologic measures. I will receive formal training in each of these specific research areas under the supervision of expert consultants. Such training will lay the foundation for a career of clinical investigation into the physiology of perimenopausal depression and the impact of hot flushes on sleep, mood, and quality-of-life.